A Dose-Escalating Study With the Fetal Estrogen Estetrol in Healthy Men.

Context: Luteinizing hormone-releasing hormone (LHRH) agonists have replaced estrogens for endocrine treatment of advanced prostate cancer (PC) because of cardiovascular side effects. The fetal estrogen estetrol (E4) may be safer for PC treatment and is expected to decrease testosterone (T) and prevent estrogen deficiency. Objective: To investigate the safety and T-suppressive effect of E4 in healthy men. Design: Double-blind, randomized, placebo-controlled, dose-escalating study. Setting: The study was conducted at a phase I clinical unit (QPS, Netherlands). Participants: Healthy male volunteers aged 40 to 70 years. Intervention(s): Three treatment cohorts of 15 volunteers with placebo (n = 5) and E4 (n = 10). Estetrol doses tested were 20, 40, and 60 mg/d. Subjects were treated for 4 weeks. Main Outcome Measures: Subjective side effects, pharmacodynamic effects on hemostatic variables, lipids, glucose, bone parameters, and endocrine parameters related to T metabolism. Results: Total and free T decreased dose-dependently and significantly. Nipple tenderness occurred in 40% and decrease of libido occurred in 30% of E4-treated men. The unwanted estrogenic effects on hemostasis were small, dose dependent, and in some cases significant. Lipid and bone parameters showed a favorable trend. Conclusion: The effect of E4 on testosterone levels is insufficient for standalone PC treatment. Taking all clinical and pharmacodynamic variables into consideration, a daily dose of 40 mg E4 seems safe for further evaluation of endocrine PC treatment in combination with LHRH analogs.

The use of high-dose estrogens for the treatment of breast cancer.

Estrogens are known to stimulate the growth of breast cancer but they are also an effective treatment for this disease (this has been termed the 'estrogen paradox'). The fact that estrogens can be an effective treatment for breast cancer is something that has almost been forgotten, whereas the fear for estrogens remains. This paper reviews the use of estrogens for the treatment of breast cancer and identifies possible applications. The data summarised in this review demonstrate that high-dose estrogens are effective for the treatment of advanced breast cancer, both as first-line treatment as well as for treatment after occurrence of endocrine resistance to TAM and AIs. Essential for efficacy is an extended period of estrogen deprivation before the tumour is subject to estrogen treatment (the gap hypothesis). Research on the mechanism of action has shown that apoptosis induced by estrogens is regulated via the estrogen receptor and growth factor signalling pathways. High-dose estrogens have a negative safety image, especially in terms of side-effects and increased rates of cardiovascular disease, but the safety data reviewed in this paper do not give rise to major concerns. Taking into account their side-effect profile together with their observed clinical efficacy, high-dose estrogens should be considered a valuable alternative to chemotherapy in selected patients.

Quantifying phenotypic flexibility as the response to a high-fat challenge test in different states of metabolic health.

Metabolism maintains homeostasis at chronic hypercaloric conditions, activating postprandial response mechanisms, which come at the cost of adaptation processes such as energy storage, eventually with negative health consequences. This study quantified the metabolic adaptation capacity by studying challenge response curves. After a high-fat challenge, the 8 h response curves of 61 biomarkers related to adipose tissue mass and function, systemic stress, metabolic flexibility, vascular health, and glucose metabolism was compared between 3 metabolic health stages: 10 healthy men, before and after 4 wk of high-fat, high-calorie diet (1300 kcal/d extra), and 9 men with metabolic syndrome (MetS). The MetS subjects had increased fasting concentrations of biomarkers representing the 3 core processes, glucose, TG, and inflammation control, and the challenge response curves of most biomarkers were altered. After the 4 wk hypercaloric dietary intervention, these 3 processes were not changed, as compared with the preintervention state in the healthy subjects, whereas the challenge response curves of almost all endocrine, metabolic, and inflammatory processes regulating these core processes were altered, demonstrating major molecular physiologic efforts to maintain homeostasis. This study thus demonstrates that change in challenge response is a more sensitive biomarker of metabolic resilience than are changes in fasting concentrations.

Validation of an FFQ and options for data processing using the doubly labelled water method in children.

OBJECTIVE: To validate an FFQ designed to estimate energy intake in children against doubly labelled water (DLW). To investigate how quality control and standard beverage portion sizes affect the validity of the FFQ. DESIGN: Thirty healthy children, aged 4-6 years, participated. Total energy expenditure (EE) was measured by the DLW method during an observation period of 15 d. At the end of this period parents filled out an FFQ designed to assess the child's habitual energy intake (EI) of the preceding four weeks. SETTING: Validation study in The Netherlands. SUBJECTS: Thirty healthy children (fifteen boys and fifteen girls), aged 4-6 years. RESULTS: Mean EI (6117 (sd 1025) kJ/d) did not differ significantly from mean EE (6286 (sd 971) kJ/d; P = 0·15); the mean EI:EE ratio was 0·98. The Pearson correlation coefficient between EI and EE was 0·62. The Bland-Altman plot showed no systematic bias and a constant bias close to zero. Less intensive quality control of the FFQ maintained the mean EI:EE ratio and decreased the correlation slightly. Using standard instead of individually measured beverage portion sizes decreased the mean EI:EE ratio, but maintained the correlation. CONCLUSIONS: It can be concluded that the developed FFQ is a valid instrument to estimate mean energy intake in a group of 4- to 6-year-old children and performs reasonably well to rank the subjects with respect to energy intake. It is therefore a useful instrument to estimate energy intake in children in surveys and epidemiological studies in The Netherlands.

Lifestyle factors of a five-year community-intervention program: the Hartslag Limburg intervention.

BACKGROUND: Community-based health promotion is a widely advocated strategy in public health to favorably alter lifestyle. The aim of this study was to investigate the net effect of a cardiovascular disease-prevention program (Hartslag Limburg) on lifestyle factors after 5 years of intervention (1998-2003). METHODS: In a cohort study, 5-year mean changes in lifestyle factors (energy intake; fat intake; time spent on leisure-time physical activity; walking, bicycling, and sports; and smoking behavior) between subjects from the intervention area (n=2356) and the control area (n=758) were compared for men and women and for those with a low (less than intermediate secondary education) and a moderate (intermediate vocational or higher secondary education) or high (higher vocational education or university) educational level. Adjustments were made for age and the mean of the individual pre- and post-intervention measurement of the variable under study. When stratifying for gender, adjustments were made for educational level, and vice versa. RESULTS: In general, lifestyle factors changed unfavorably in the control group, whereas changes were less pronounced or absent in the intervention group. The adjusted difference in mean change in lifestyle factors between the intervention group and the control group was significant (p